Core Skeleton Research Articles

Solid-Phase Parallel Synthesis of N-Substituted-2-aminothiazolo[4,5-b]pyrazine Derivatives via Tandem Reaction of Isothiocyanate Terminated Resin with o-Bromo-2-Aminopyrazines.

A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is the tandem reaction of isothiocyanate terminated resin 2 with o-bromo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo[4,5-b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated N-alkyl-, N-acyl-, and N-sulfonyl-2-aminothiazolo[4,5-b]pyrazine derivatives. The physicochemical properties and the polar surface areas of synthesized compounds were evaluated.

Correction to "A Biomimetic Route for Construction of the [4+2] and [3+2] Core Skeletons of Dimeric Pyrrole-Imidazole Alkaloids and Asymmetric Synthesis of Ageliferins".

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “A Biomimetic Route for Construction of the [4+2] and [3+2] Core Skeletons of Dimeric Pyrrole–Imidazole Alkaloids and Asymmetric Synthesis of Ageliferins”Xiao Wang, Xiaolei Wang, Xianghui Tan, Jianming Lu, Kevin W. Cormier, Zhiqiang Ma, and Chuo Chen*Cite this: J. Am. Chem. Soc. 2016, 138, 43, 14505Publication Date (Web):October 19, 2016Publication History Published online19 October 2016Published inissue 2 November 2016https://doi.org/10.1021/jacs.6b09697Copyright © 2016 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1393Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (248 KB) Get e-Alerts Get e-Alerts

The Study of Effect of Pore Structure on Oil Displacement Efficiency of Polymer Flooding

Characteristics of pore structure have an important influence on the development of water flooding. In order to improve the recovery rate, it is important to investigate the relationship between pore structure and oil displacement efficiency. The permeability of the artificial cores in this experiment is 189×10-3μm2, 741×10-3μm2and 21417×10-3μm2. We used the CT technology method to scan the pore structure of the three cores, and did oil displacement experiment to investigate the effect of pore structure on the oil displacement efficiency. The result shows that the pore and throat common affect oil displacement efficiency: the bigger the pore and throat radius, the better is the oil displacement efficiency; the smaller the pore and throat radius, the worse is the oil displacement efficiency. The experiment studied the influence of pore structure on oil displacement efficiency deep into microcosmic pore structure without damaging the core skeleton, thereby improving the basis of oil recovery from the micro level and the mechanism.

Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A3 and A2A subtypes

The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A3 or the hA2A receptor subtype. The N8-(hetero)arylcarboxyamido substituted compounds 4–14 and 21–30, bearing a 6-phenyl moiety or not, respectively, show good hA3 receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA2A receptor subtype (compounds 31–38) and also the 6-phenyl analogues 18–20 do not bind the hA2A AR, or show hA1 or balanced hA1/hA2A AR affinity in the micromolar range. Molecular docking of the new hA3 antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA3 receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA3 antagonists herein reported, i.e. the 2,6-diphenyl-8-(3-pyridoylamino)imidazo[1,2-a]pyrazine 29, tested in a rat model of cerebral ischemia, delayed the occurrence of anoxic depolarization caused by oxygen and glucose deprivation in the hippocampus and allowed disrupted synaptic activity to recover.

ChemInform Abstract: Unparalleled Ease of Access to a Library of Biheteroaryl Fluorophores via Oxidative Cross‐Coupling Reactions: Discovery of Photostable NIR Probe for Mitochondria.

The development of straightforward accesses to organic functional materials through C–H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor–acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C–H/C–H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm–1 in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostabilit...

(Invited) X-Ray Crystallographical Studies on the Intermediates in the Solution Fabrication Process for Highly Efficient Perovskite Solar Cells

Perovskite solar cells represent cost-effective next generation printable photovoltaics. In a relatively short period, power conversion efficiencies (PCEs) in such cells have been substantially increased, mainly due to improvements of the fabrication protocols for the perovskite layer as well as the development of new materials for buffer layers. In this presentation, the recent progress and perspective on this promising new type of photovoltaics are introduced, including our approaches toward development of high PCE cells in terms of materials science. Regarding the molecular design for organic semiconductors that are used as p-type buffer layer in perovskite solar cells, we have recently reported that the use of partially oxygen-bridged triarylamines as quasiplanar scaffolds for charge-transporting materials facilitates delocalized pi-conjugation and on-top pi-stacking in the solid state, which ensures high carrier mobilities in the pi-stacking direction. In this study, we designed and synthesized the two-dimensionally expanded system (HND-Azulene) with a sheet-shaped structure, in which four oxygen-bridged triarylamines that contain alkoxy groups to enhance the solubility were attached to an azulene core skeleton. Using HND-Azuleneas a HTM in perovskite solar cells led to high PCEs (16.5%), even compared to Spiro-OMeTAD. By comparison with reference compounds, we were able to determine the key factors that improve the efficiency of HTMs in perovskite solar cells, which ultimately led to an increase in cell performance. Moreover, we focused on the fabrication of perovskite layer by one-step solution method with solvent engineering, and studied on the mechanism in terms of the elucidation of the key intermediates formed during the process and the roll of solvents. Based on these results, we could develop and optimize the fabrication protocol to obtain dense and planar perovskite layer with 500 nm thickness. Using this protocol, we achieved to prepare the perovskite solar cells with high PCEs over 20%. The details of our recent progress will also be discussed in this presentation.

Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion.

The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential antimetastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of the P2X7R antagonist 7 were performed. The structure-activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R1 position and the substituted position and overall size of R2 for P2X7R antagonism. The optimized novel analogues displayed potent P2X7 receptor antagonism (IC50 = 0.11-112 nM) along with significant suppressive effects on IL-1β release (IC50 = 0.32-210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting the potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.

Concise Synthesis of Astellatol Core Skeleton.

A ten-step, enantiospecific synthesis of the highly challenging core skeleton of sesterterpenoid astellatol has been achieved. Key transformations of this strategy include a facile, convergent construction of the tricyclic motif and a SmI2 -induced reductive radical cyclization that forms the pivotal cyclobutane ring.

Synthetic studies on the application of the intramolecular azide-alkene 1,3-dipolar cycloaddition reaction in the construction of the core structure of complex alkaloids

Synthesis of the core skeletons of the polycyclic alkaloids lycopodine and porantherine has been accomplished employing as a key step an Intramolecular Azide-Olefin Cycloaddition reaction (IAOC)/enamine addition/Mannich cascade reaction. Applying this methodology, the first synthesis of C15-desmethyl lycopodine has been developed.

Synthesis of the Cortistatin Pentacyclic Core by Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling.

The pentacyclic core skeleton of the cortistatins has been prepared in a stereoselective fashion by strategic use of an alkoxide-directed metallacycle-mediated annulative cross-coupling. This metal-centered tandem reaction delivers a polyunsaturated hydrindane and establishes the C13 stereodefined quaternary center with high levels of stereocontrol. Subsequent regio- and stereoselective global hydroboration results in the realization of the DE-trans ring fusion and a tertiary alcohol at C8. Establishment of the ABC-tricyclic subunit was then accomplished through phenolic oxidation/trans-acetalization, chemoselective reduction, regioselective cleavage, and intramolecular alkylation at C5.

Synthesis and structure–activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy

Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(−). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS–HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(−) breast cancer cells (MDA-MB-231). Thus, the FcOBHS–HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer.

Unparalleled Ease of Access to a Library of Biheteroaryl Fluorophores via Oxidative Cross-Coupling Reactions: Discovery of Photostable NIR Probe for Mitochondria.

The development of straightforward accesses to organic functional materials through C-H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor-acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C-H/C-H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm(-1) in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostability. Indazo-Fluor 5h exhibits superior photostability and very low cytotoxicity, which would be a prominent reagent for in vivo mitochondria imaging.

Paecilonic acids A and B, bicyclic fatty acids from the jellyfish-derived fungus Paecilomyces variotii J08NF-1

Two new bicyclic fatty acids, paecilonic acids A and B (1 and 2), were isolated from the culture broth of the marine fungus Paecilomyces variotii derived from the jellyfish Nemopilema nomurai. Compounds 1 and 2 share the same molecular formula and possess a 6,8-dioxabicyclo[3.2.1]octane core skeleton. The planar structures of compounds 1 and 2 were established by spectroscopic analysis, which included NMR and ESI-MS/MS. Relative and absolute configurations were determined by analyzing coupling constants, NOESY correlations, and optical rotations.

Structural Revisions of a Class of Natural Products: Scaffolds of Aglycon Analogues of Fusicoccins and Cotylenins Isolated from Fungi.

The reisolation and structural revision of brassicicene D is described, and inspired us to reassign the core skeletons of brassicicenes C-H, J and K, ranging from dicyclopenta[a,d]cyclooctane to tricyclo[9.2.1.0(3,7)]tetradecane using quantum-chemical predictions and experimental validation strategies. Three novel, highly modified fusicoccanes, brassicicenes L-N, were also isolated from the fungus Alternaria brassicicola, and their structures were unequivocally established by spectroscopic data, ECD calculations, and crystallography. The reassigned structures represent the first class of bridgehead double-bond-containing natural products with a bicyclo[6.2.1]undecane carbon skeleton. Furthermore, their stabilities were first predicted with olefin strain energy calculations. Collectively, these findings extend our view of the application of computational predictions and biosynthetic logic-based structure elucidation to address problems related to the structure and stability of natural products.

ChemInform Abstract: Synthesis of Azabicycles via Cascade Aza‐Prins Reactions: Accessing the Indolizidine and Quinolizidine Cores.

The first detailed studies of intramolecular aza-Prins and aza-silyl-Prins reactions, starting from acyclic materials, are reported. The methods allow rapid and flexible access toward an array of [6,5] and [6,6] aza-bicycles, which form the core skeletons of various alkaloids. On the basis of our findings on the aza-Prins and aza-silyl-Prins cyclizations, herein we present simple protocols for the intramolecular preparation of the azabicyclic cores of the indolizidines and quinolizidines using a one-pot cascade process of N-acyliminium ion formation followed by aza-Prins cyclization and either elimination or carbocation trapping. It is possible to introduce a range of different substituents into the heterocycles through a judicial choice of Lewis acid and solvent(s), with halo-, phenyl-, and amido-substituted azabicyclic products all being accessed through these highly diastereoselective processes.

Identification of a Small Benzamide Inhibitor of Influenza Virus Using a Cell-Based Screening

Background: The zoonotic transmission of highly pathogenic avian influenza viruses and the global pandemic of H1N1 influenza in 2009 signified the need for a wider coverage of therapeutic options for the control of influenza. Methods: An in-house compound library was screened using a cytopathic effect inhibition assay. Selected hits were then tested in vivo and used as a core skeleton for derivative synthesis. Results: The hit compound (BMD-2601505) was effective [50% effective concentration (EC₅₀) of 60-70 μ<smlcap>M</smlcap>] in reducing the death rate of cells infected with human influenza A and B viruses as well as avian influenza A virus. Furthermore, BMD-2601505 reduced the weight loss and increased the survival after lethal infection. The compound was further modified to enhance its antiviral potency. Results show that one derivative with bromobenzene moiety was most effective (EC₅₀ of 22-37 μ<smlcap>M</smlcap>) against the influenza viruses tested. Conclusion: We identified a small benzamide compound exhibiting antiviral activity against influenza viruses. The results warrant further evaluation of antiviral activities against drug-resistant influenza isolates.

Enantioselective total synthesis of (+)-Lingzhiol via tandem semipinacol rearrangement/Friedel-Crafts type cyclization.

Enantioselective total synthesis of (+)-Lingzhiol has been achieved. It is the first example of in tandem semipinacol rearrangement reactions, the migrated aryl group further reacting with the carbonyl oxonium electrophile to furnish a polycyclic skeleton. Our synthesis involves 13 steps and proceeds in 6% overall yield.

Skeleton selectivity in complexation of chelerythrine and chelerythrine-like natural plant alkaloids with the G-quadruplex formed at the promoter of c-MYC oncogene: in silico exploration

Chelerythrine binds at the 5′ end and arrests the G-quadruplex formed in the promoter region ofc-MYConcogene thus restrict thec-MYCexpression. Position of methoxy group over the core skeleton of chelerythrine determines the binding pattern of ligand.

A Unified Strategy to Plakortin Pentalenes: Total Syntheses of (±)-Gracilioethers E and F.

A unified route to oxygenated Plakortin pentalenes is described. Along with the previously disclosed total synthesis of hippolachnin A, the potential of this scheme is demonstrated by the first total synthesis of gracilioether E, as well as the total synthesis of gracilioether F. Key features of the unified synthetic strategy include the concise construction of common key intermediate 1 and a topological-strategy guided functionalization of a highly substituted cyclobutene providing efficient access to the core skeletons.

Rational Improvement of Molar Absorptivity Guided by Oscillator Strength: A Case Study with Furoindolizine‐Based Core Skeleton

AbstractThe rational improvement of photophysical properties can be highly valuable for the discovery of novel organic fluorophores. Using our new design strategy guided by the oscillator strength, we developed a series of full‐color‐tunable furoindolizine analogs with improved molar absorptivity through the fusion of a furan ring into the indolizine‐based Seoul fluorophore. The excellent correlation between the computable values (oscillator strength and theoretical S0–S1 energy gap) and photophysical properties (molar absorptivity and emission wavelength) confirmed the effectualness of our design strategy.